1,2-dihydroquinobenzoxazepine(piperazinylalkyl)oximes

ABSTRACT

1,2-DIHYDROQUINOBENZOXA(OR THIA)ZEPINE DERIVATIVES ARE PROVIDED HAVING THE STRUCTURES   A&lt;(-CH2-((Y)N&#39;&#39;-1,2-PHENYLENE)-(4-(R1-N(-R2)-Z-O-N=),(X)N-   1,2,3,4-TETRAHYDROQUINOL-1,8-YLENE)-) OR   A&lt;(-CH2-(4-(R1-N(-R2)-Z-O-N=),(Y)N&#39;&#39;-1,2,3,4-TETRAHYDRO-   QUINOL-8,1-YLENE)-((X)N-1,2-PHENYLENE)-)   WHEREIN A IS O OR S; X AND Y ARE THE SAME OR DIFFERENT AND CAN BE HALOGEN, TRIFLUOROMETHYL, LOWER ALKYL, CYCLOALKYL, LOWER ALKYLMERCAPTO, LOWER ALKOXY, CYANO, ISOCYANIDO OR DI-LOWER ALKYLSULFAMOYL; R1 AND R2 ARE THE SAME OR DIFFERENT AND CAN BE HALOGEN, LOWER ALKYL, ARALKYL OR ALKENYL OR NR1R2 TAKEN TOGETHER IS A HETEOCYCLIC RADICAL HAVING THE FORMULA   -N&lt;(-(CH2)R-X&#39;&#39;-CH2-CH2-)(-R3)   IN WHICH X&#39;&#39; REPRESENTS NR4, O, S, OR CH2; R REPRESENTS 1, 2 OR 3; R4 REPRESENTS HALOGEN, LOWER ALKYL, HYDOXY-LOWER ALKYL, LOWER ALKANOYLOXY-LOWER ALKYL, HYDROXYL-LOWER ALKOXY-LOWER ALKYL, DI(LOWER AKYL) AMINO-LOWER ALLOWER ALKYL, LOWER-ALKYLAMINO-LOWER ALKYL, DI-LOWER ALKYL AMINO-LOWER ALKYL, AINO-LOWER ALKYL, DILOWER ALKYL OF THE R4 GROUP; X IS ALKYLENE OR ALKENYLENE; N IS 0, 1 OR 2 AND N&#39;&#39; IS 0, 1 OR 2; AND PHARMACEUTICALLY ACCEPTABLE SALT; THEREOF.

United States Patent 3,813,396 1,2-DIHYDROQUINOBENZOXAZEPINEEIPER-AZINYLALKYL1OX11VIES Harry L. Yale, New Brunswick, and Ramesh B.Petigara,

Somerset, N.J., assignors to E. R. Squibb & Sons, Inc., Princeton, NJ.No Drawing. Filed Aug. 13, 1971, Ser. No. 171,715 Int. Cl. C07d 51/70US. Cl. 260-268 PC 8 Claims ABSTRACT OF THE DISCLOSURE1,2-dihydr0quinobenzoxa(or thia) zepine derivatives are provided havingthe structures A-CH (XL. b. CH {/7 wherein A is O or S; X and Y are thesame or difierent and can be halogen, trifluoromethyl, lower alkyl,cycloalkyl, lower alkylmercapto, lower alkoxy, cyano, isocyanido ordi-lower alkylsulfamoyl; R and R are the same or different and can behalogen, lower alkyl, aralkyl or alkenyl or NR R taken together is aheterocyclic radical having the formula The present invention relates toaminoalkyl ethers of 1,2-dihydroquinobenzoxa (or thia) zepinederivatives of the structure Patented May 28, 1974 wherein X and Y arethe same or different and can be halogen, trifluoromethyl, lower alkyl,cycloalkyl, lower alkylmercapto, lower alkyloxy, cyano, isocyanido ordilower alkylsulfamoyl, A is O or S, Z is alkylene or alkenylene, n is0, 1 or 2 and n is 0, 1 or 2, and pharmaceutically acceptableacid-addition salts thereof.

The term lower alkyl as employed herein includes both straight andbranched chain radicals of up to and including eight carbon atoms, forinstance, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl and the like.

The term halogen includes F, C1, or Br or I.

The lower alkylmercapto groups contain up to eight carbon atoms andinclude methylmercapto, ethylmercapto, propylrnercapto and mercaptoradicals containing any of the lower alkyl groups mentionedhereinbefore.

The terms lower alkyloxy and lower alkoxy are interchangeable and referto groups containing up to eight carbon atoms and which include any ofthe lower alkyl groups mentioned hereinbefore attached to an oxygenatom.

The term cycloalkyl includes saturated ring systems containing fromthree to seven carbons such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

The term alkenyl includes mono-unsaturated straight chain or branchedchain radicals of less than eight carbons corresponding to lower alkylas defined above.

The alkylene or alkenylene group represents a divalent straight orbranched chain aliphatic hydrocarbon and can contain from one to sixcarbon atoms in a chain with or without side chains. The side chains caninclude cycloalkyl substituents. Examples of these groups include groupscorresponding to the above alkyl or alkenyl groups.

In the above Formulae I and II, each of the carbocyclic aromatic ringscan include 0, 1 or 2 substituents, other than hydrogen. The nature andposition of the substituents in the starting materials will determinewhich isomer, Type I and/or Type H, is obtained.

R and R may be the same or different and represent hydrogen, loweralkyl, aralkyl and alkenyl; NR R taken together is a heterocyclicradical having the formula in which X represents NR, 0, S or CH rrepresents 1, 2 or 3; R represents hydrogen, lower alkyl, hydroxyloweralkyl, lower alkanoyloxy-lower alkyl, hydroxylower alkoxy-lower alkyl,di(lower alkyl)amino-lower alkoxy-lower alkyl, lower-alkylamino-loweralkyl, di-lower alkyl amino-lower alkyl, amino-lower alkyl; and Rrepresents any of the R groups. These may be exemplified by piperidinyl;(lower alkyl)-piperidinyl [e.g., 2-, 3- or 4-(lower alkyl)piperidinyl];(lower alkoxy)piperidinyl; pyrrolidinyl; (lower alkyl)-pyrrolidinyl;(lower alkox'y) pyrrolidinyl; piperazinyl; (lower alkyl)piperazinyl(e.g., N -methylpiperazinyl); di(lower alkyl)piperazinyl; (loweralkoxy)piperazinyl; (hydroxy-lower alkyl)piperazinyl [e.g., N-(2-hydroxyethyl)piperazinyl]; (lower alkanoyloxyalkyl)piperazinyl[e.g., N (2 acetoxyethyDpiperazinyl]; (hydroxy-lower alkoxy-loweralkyl)piperazinyl [e.g., N -[2 (2 hydroxyethoxy)ethyllpiperazinyl]; di-(lower alkyl)amino-(lower alkoxy-lower alkyl)piperazinyl [c.g., N-[2-(2-dimethylaminoethoxy)ethyl1piperazinyl]; homopiperazinyl;amino(lower alkyl)piperidinyl [e.g., 3-(aminomethyl)piperidinyl], loweralkylamino (lower alkyl)piperidinyl [e.g., 2-[(methylamino)ethyl]piperidinyl], di-lower alkylaminoflower alkyl)piperidinyl [e.g., 4-[dimethylamino)methyl) ]piperidinyl] The salts of the compounds of thisinvention include the acid-addition salts, particularly the non-toxicacidaddition salts. Acids useful for preparing the acid-addition salts,include inter alia, inorganic acids, such as the hydrohalic acids (e.g.,hydrochloric and hydrobromic acid), sulfuric acid, nitric acid andphosphoric acid, and organic acids, such as oxalic, maleic, fumaric,tartaric, citric, pamoic, acetic, and succinic acid.

As will be seen hereinafter, the compounds of the invention are preparedfrom starting materials of the structure (lHzCHz C O H Where in thestarting material II, n is 1 or 2 and X includes a stronglyelectronegative group like trifluoromethyl, cyano, isocyanido ordi-lower alkylsulfamoyl substituent at the 7-position, and n is 0, or Yis a substituent at a position other than 3 and 4 in the startingmaterial, cyclization is directed to the 4-position so that the Type IIisomer is subsequently formed. However, where X is an ortIto-paraorienting group like halogen, especially chlorine, and n is 1 or 2 andat least one halogen is at the 7-position of starting material III, or Yis lower alkyl, lower alkyloxy, cycloalkyl or lower alkylmercapto at anyposition or a strongly electronegative group at a position other than 3,or when n is O, a mixture of the Type I and Type H isomers is obtained.

Where in the starting material III, n is l or 2 and Y includes astrongly electronegative group like trifluoromethyl, cyano or di-loweralkylsulfamoyl at the 3-position, and n is 0 or X is a substituent at aposition other than 7 in the starting material, cyclization is directedto the 6-position so that the Type I isomer is subsequently formed.

Where in the starting material III, n is 1 or 2 and Y A-CH:

Where the starting material does not include substituents at the 3and/or 7 positions, but does include substituents such as lower alkyl,lower alkyloxy, cycloalkyl or lower alkylmercapto at the 2, 8 and/or 9positions, the Type I isomer is obtained.

Where the starting material does not include substituents at the 3and/or 7 positions, but does include strongly electronegative groups atthe 1 and/or 9 positions, the Type I isomer is obtained. However, wherethe starting material includes a strongly electronegative group at the 2and/or 8 positions, then a mixture of the Type I and Type H isomers isobtained.

Where X represents a strongly electronegative group liketrifiuoromethyl, cyano or di-lower alkylsulfamoyl and n is 1 or 2 atleast one X being at the 7-position of the starting material and Y islower alkyl, lower alkylmercapto, cycloalkyl or lower alkoxy at anyposition or any of the above strongly electronegative groups at aposition other than 3 in the starting material and n is 0, 1 or 2, theType II isomer is obtained.

Where X is lower alkyl, lower alkyloxy, cycloalkyl, or loweralkylmercapto and n is 1 or 2 and Y is halogen, trifluoromethyl, cyano,isocyanido or di-lower alkylsulfamoyl, and n is l or 2 at least one Ybeing at the 3-position of the starting material, the Type I isomer isobtained. In this case, X can be trifluoromethyl or other stronglyelectronegative group so long as it is not in the 7- posi-tion of thestarting material as will be seen hereinafter.

Where X is lower alkyl, lower alkyloxy, cycloalkyl or lowerallcylmercapto, and n is 1 or 2 and n in (Y) is 0, the Type I isomer isobtained.

Where Y is lower alkyl, lower alkyloxy, cycloalkyl or loweralkylmercapto and n is 1 or 2 and the n in (X) n is 0, the Type IIisomer is obtained.

Where both X and Y represent lower alkyl, lower alkoxy and/ or loweralkylmercapto, at least one of said groups being at the 3 and 7positions of the starting material, the Type I isomer is obtained.

Preferred are those compounds of Formula I wherein n=0 and n'=0 and A=O;those compounds ofFormula I wherein 11:0, n'=l and Y is Cl at thell-position, and n: 1, n' =O, and X is Cl 'at 4 position and A=O andthose compounds of Formula II wherein 11:1, X is CF or Cl at thell'-position, n=0, and A=O.

The compounds of the invention of Formulae I and II can be prepared byreacting an oxime of Formula V or VI N C BIO-Ni) VII wherein Q ishalogen or tosyloxy and Z and R and R are as defined above, however inthis case R and R are other than hydrogen.

Compounds wherein one of the R and R groups is hydrogen are prepared inthe following manner. 5 When the oxime, V or VI, or the anion thereof,is reacted with a haloalkylamine in which R or R is benzyl, then, thatgroup in I or II can be selectively eliminated by reaction with ahaloformate of the structure 0 1O VIIa R i l-Hal wherein R is alkyl,aralkyl or aryl, such as ethyl chloroformate or benzyl chloroformate, togive I or II in which R or R is a carboethoxy group. The carboethoxygroup can then be selectively replaced with hydrogen, by treatment witha halogen acid, e.g., hydrogen bromide.

When the oxime, V or VI, or the anion thereof is reacted with ahaloalkylamine in which R or R is formyl, then that group in I or II canbe selectively replaced with hydrogen by treatment with either mineralacid or inorganic base, e.g., hydrochloric acid or sodium hydroxide.

In the above methods, the oxime is first converted to an anion byreaction with a base such as sodium hydride in non-protic solvents likebenzene, toluene, dimethylformamide, dimethylsulfoxide, tetrahydrofuran,or heptane, or with a base such as an alkali metal hydroxide, forexample sodium hydroxide, in solvents such as acetone or 2-butanone, orwith an alkali or alkaline earth metal alkoxide, e.g., sodium ethoxide,in a solvent such as dimethylformamide.

In another method, the anion is reacted with a haloalkylene halide orhaloalkyenylene halide of the structure wherein Hal and Hal can be Brand Cl, respectively, C1 and F respectively, I and Br, respectively, Brand F, respectively, etc. to form the corresponding ether of thestructure A-CH:

N c HavzoN=U 6 which is reacted with an amine of the structure XII I-INRR to form compounds of formula I and II.

In another method for preparing compounds of structures I and II, the3-one or 3'-one XIV are reacted with an aminoalkyleneoxyamine oraminoalkenyleneoxyamine of the structure XV H,,NO-ZNR R The 3-onestarting materials (XIII and XIV) of the invention can be prepared byreacting a compound of the structure III A-CHg N CH (JHgCHzCOOH whereinX, Y, n, n, and A are as defined hereinbefore, with a phosphoruspentahalide, such as phosphorus pentachloride, in a molar ratio ofIIIzpentahalide of within the range of from about 0.9:1 to about 1:1, inthe absence of oxygen, and in the presence of an inert solvent, such asbenzene, toluene, xylene, pentane, hexane, etc., at a temperature withinthe range of from about 0 to about 10 C., to form an acyl halide of thestructure A-CH,

c N or: II dmcniooou with trifluoroacetic anhydride or phosphoruspentoxide,

in a molar ratio of IIIztrifluoroacetic anhydride, or phosphoruspentoxide within the range of from about 0.9:1 to about 1:1, in thepresence of an inert solvent such as benzene, toluene, xylene, pentane,hexane, etc., at a temperature Within the range of from about 10 toabout 7 C., or with polyphosphoric acid (PPA) in a molar ratio ofIII:PPA of within the range of from about 1:10 to about 1:25.

The ketones of formulae XIII and XIV react with hydroxylamine or thehydrohalide salt thereof in the presence of a solvent such as ethanol,methanol, etc., to give the corresponding oxime starting materials (Vand VI), that is The starting materials of formula IH are prepared by asequence of reactions. One step comprises reacting compounds having theformula:

XVII A-CH;

with acrylonitrile to yield compounds of formula XVIII AH CH; C N

wherein n, n, X, Y and A are as defined herein.

This reaction is carried out by employing an excess of the acrylonitrileas the solvent. The temperature utilized in the reaction can be variedfrom about to about 100 C. with the preferred range being between about0 and about 75 C. This reaction proceeds expeditiously when a smallamount (up to about 1%) of a strong base like sodium hydroxide, sodiummethoxide, potassium t-butoxide, or benzyl trimethylammonium hydroxide(Triton B) is used as the catalyst.

The next step for preparing compounds of formula III is to treat thecompounds of structure XVIII with alcoholic hydrogen halide, such ashydrogen chloride in methanol, ethanol, and so forth, at roomtemperature whereby esters of the structure XIX are formed.

(LIBCHZC wherein R is lower alkyl.

By saponifying compound XIX with an alkali metal hydroxide, e.g.,potassium hydroxide, lithium hydroxide, and so forth, the desiredcarboxylic acids of structure III can be obtained.

Examples of compounds of formula XVII where A is S are set out in US.Patents Nos. 3,188,321 and 3,188,- 322.

Examples of compounds of Formula XVIII where A is O or S can be found ina paper entitled Novel Polycyclic Heterocycles, by Yale et al., J. Med.Chem. 13, 713 (1970).

Examples of starting materials which can be employed in preparing thecompounds of the invention include, but are not limited to, thefollowing wherein A can be 0 or S.

OH N

CHaCHuC O OH CHzCHz C O OH 3. A-CH:

CH N C l CHiCHjC O OH CHzCHz C O O H 5. A-CH:

/ Cl N on AHzCHa C O O H (EHzOHzGOOH HzCHzCOOH 8. A-CH:

H N H A-CH:

F30 CH;

CH N H JHQCHz C O OH N 43H: CH; C O O H A-CH:

CH N

CH2 CH1 C O O H A-CH:

CFs CH\N/ CH CH CHz C O O H A-CH:

(lH CHaCO OH CH CH C O OH A-CH:

CH III a CHaCHaCOOH onion; 0 on .ACH2 clia q @CH: C III C CHgCHg C O OHCH III CI-hCH CO OH A-CHg CgHy,

( lHaCHn C O OH 23. on, I CH;

A-CH: I CH3 on, Q E

H N on OHzCH: O O OH Compounds of this invention are therapeuticallyactive compounds which are utilizable as central nervous systerndepressants, as muscle relaxants and an anti-inflammatory agents. Forthese purposes, they may be administered orally or parenterally in suchform as tablets, capsules, injectables, or the like by incorporating theappropriate dosage of the compound with carriers according to acceptedpharmaceutical practices.

The new compounds of formulae I and II are also useful as antimicrobialagents and may be used to combat infections in animal species, such asmice, rats, dogs, guinea pigs and the like, due to organisms such asTrichomonas vaginalis, T richomonas foetus, Staphyloccocus aureus,Salmonella schottmuelleri, Klebsiella pneumoniae, Proteus vulgaris,Escherichia coli, C. albicans or Trichophyton mentagraphytes. Forexample, a compound or mixture of compounds of formulae I and II may beadministered orally to an infected animal, e.g., to a mouse, in anamount of about 5 to 25 mg. per kg. per day in 2 to 4 divided doses.These may be conventionally formulated in a tablet, capsule or elixircontaining about 10 to 250 mg. per dosage unit, by compounding theactive substance or substances With the conventional excipient, vehicle,binder, preservative, flavor, etc., as called for by acceptedpharmaceutical practice. They may also be applied topically, e.g., todermatophytosis in a guinea pig, in a lotion, salve or cream at aconcentration of about 0.01 to 3 percent by Weight.

They may also be used as surface disinfectants, About 0.01 to 1 percentby weight of any of these substances may be dispersed on an inert solidor in a liquid such as water and applied as a dust or spray. They may beincorporated also, for example, in a soap or other cleansing agent,e.g., a solid or liquid detergent, detergent composition, for example,in general cleaning, in cleaning dairy barns or equipment or cleaningfood handling or processing equipment.

EXAMPLE 1 1,2 dihydro-1 l-(trifiuoromethyl) -3 Ii,7g-quino [8,1-cd1 1,5]-benzoxazepin-3-one, 3- (4-methyl-l-piperazinyl) propyl] -oxime,dihydrochloride I. 1,2-dihydro-1l-(trifluoromethyl)GEJE-quino [8,1-cd][1,51benzoxazepin-3-one A. 5,11dihydro-7-(trifluoromethyl)dibenz[b,e][1,4]

oxazepine-5 propionic acid: To 50.0 g. of 5,ll-dihydro-7-(trifiuoromethyl)dibenz-[b,e] [1,4]oxazepine in 60 ml. of distilledacrylonitrile is added in 5 minutes 0.80 ml. of Triton B. Subsequently,the mixture is heated for one hour under reflux and the product isolatedby extraction with benzene to give 5,11 dihydro-7-(trifluoromethyl)dibenz[b,e] [1,4] oxazepine 5 propionitrile, M.P. about 161-163.

7 (trifluoromethyl) 5,11 dihydrodizenz[b,e] [1,4]oxazepine-S-propionitrile, 15.0 g., is dissolved in 240 ml. of drydioxane and to this 140 ml. of 30% methanolic hydrogen chloride isadded. The solution is stirred for 36 hours, 6 ml. of B is added,stirred 0.5 hour, and then concentrated in vacuo to 120 ml. The solid isfiltered, and the filtrate is concentrated to dryness in vacuo. Theresidual liquid is taken up in 200 ml. of diethyl ether, treated withDarco and Hyflo, the diethyl ether solution is concentrated and theresidue distilled in vacuo to give 5,11- dihydro7-(trifiuoromethyl)dibenz[b,e] [1,4]-oxazepine- S-propionic acid, methylester, B.P. about 166-168 (0.08 mm.), M.P. about 70.0-71.5".

7 (trifluoromethyl) 5,11-dihydrodibenz[b,e] [1,4] oxazepine--propionicacid, methyl ester, 31.5 g., is dissolved in 3 liters of methanol and tothis 5.0 g. of potassium hydroxide dissolved in 250 ml. of water isadded. The mixture is refluxed for 2.5 hours and then concentrated invacuo. The residue is taken up in 2.5 liters of water and this solutionis acidified with 2% aqueous HCl to give 25.3 g. of5,11-dihydro-7-(trifluoromethyl) dibenz[b,e][1,4]-oxazepine-5-propionicacid, M.P. about 94-96".

B. 1,2 dihydro 11 (trifiuoromethyl)-3g,7g-quino [8,1-cd][1,5]benzoxazepin-3-one: A solution of 6.86 g. of 5,11 dihydro7(trifluoromethyl)-dibenz[ b,e][1,4] oxazepine-S-propionic acid in 50ml. of benzene is cooled to 510. To this is added dropwise with stirringat solution of 4.6 g. of P01 in 25 ml. of benzene over a period of 15minutes. The solution is stirred at 25 for 40 minutes and then at 40-50for another v minutes. The reaction mixture is then heated at 55 for 10minutes, cooled to 10 and to this is added dropwise with stirring asolution of 12.0 g. anhydrous SnCl, in 20 minutes at room temperature;100 ml. of other are added, followed by 10 ml. of concentratedhydrochloric acid, and then 100 ml. of water. After stirring vigorouslyfor 10 minutes, the organic phase is separated, and the aqueous phase isextracted with 100 ml. of ether. The combined organic extracts arewashed, dried, filtered, and concentrated to dryness to give 6.9 g. ofresidue; this is crystallized from 2- propanol to give 4.3 g. ofproduct, M.P. about 140142.

A solution of 28.0 g. of the ketone from part I(B), and 13.6 g. ofhydroxylamine hydrochloride in 600 ml. of warm 70% ethanol is refluxedfor 4 hours, and kept at room temperature to give a pale yellowcrystalline solid. This is filtered and recrystallized from 70% ethanolto give 21.0 g. of the product, M.P. about l98-200 (dec.).

III. 1,2 dihydro 11 (trifiuoromethyl)-3 ,7g-quino[8,1-cd][1,5]benzoxazepin 3 one,[3-(4-methyD-lpiperazinyl)propyl]-oxime, dihydrochloride To a suspensionof 6.0 g. of the oxime from Example 1, Part II in 100 ml. of anhydroustoluene is added 1.0 g. of 50% sodium hydride and the mixture is heatedunder reflux for 1.5 hours. T 0 this, at 10 is added, dropwise, asolution of 4.9 g. of 1-(3-chloropropyl)-4-methylpiperazine in 20 ml. oftoluene. The mixture is then heated under reflux for 4 hours, filteredand the filtrate concentrated to dryness in vacuo to give 10.1 g. ofresidue. This is dissolved in 30 ml. of 2-propanol and to this is added16 ml. of 4.8 N Z-propanolic hydrogen chloride to give 11.4 g. ofmaterial, M.P. about 220-224 (dec.). This is recrystallized from2-propanol to give 9.8 g. of the product, M.P. about 235-237".

EXAMPLE 2 1,2-dihydro 11 (trifluoromethyl)-3g-7g-quino[8,l-cd][l,5]benzoxazepin 3 one, [2-(1-pyrrolidinyl)ethyl] oxime, hydrochlorideTo the sodium salt prepared as shown in Example 1, Part ill from the 3.6g. of the oxime (Example 1, Part II), 70 ml. of toluene and 0.65 g. ofsodium hydride, is added 2 (l-pyrrolidinyl)ethyl-p-toluenesulphonate intoluene. The reaction mixture is heated under reflux for 4 hours, thencooled, washed with water, then saturated NaCl, dried and concentratedin vacuo. The residue, 4.9 g. of solid, is recrystallized from hexane togive 4.3 g. of base, M.P. about 117-119. This is converted to itshydrochloric acid salt by treating with Z-propanolic hydrogen chloride.Recrystallization from 2-propan0l gives 4.3 g. of the product, M.P.about 212-214 (dec.).

EXAMPLE 3 1,2 dihydro-1l-(trifiuoromethyl)-3 Ii,7 -quino-[8,l-cd] 1,5]-benzoxazepin-3-one, [3- (dimethylamino) pro pyl] oxime, hydrochlorideTo sodium ethoxide (from 0.5 g. of sodium in 40 ml. of absolute EtOH) isadded 5.35 g. of the oxime (Example 1, Part II), and the mixture heatedunder reflux for 2 hours. The solvent is removed and 10 ml. of MN-dimethylformamide is added and again concentrated to dryness. Theresidue is dissolved in ml. of N,N-dimethylformamide and to the solutionis added 4.0 g. of 3-chloro-N,N-dimethylpropylamine in 10 ml. of thesame solvent. The reaction mixture is heated at -110 for 4 hours and thesolvent removed in vacuo. The residue is distributed between ether-H O,the other layer is separated, the aqueous phase extracted with ether.The combined extracts are concentrated in vacuo to give a residualsolid. This is recrystallized from hexane to give 6.4 g. of the base,M.P. 94-96, and this gives 6.7 g. of the hydrochloride, M.P. about198-200 (dec.). This is recrystallized from 2-Pr0H to give 5.2 g. of theproduct, M.P. about 203204 (dec.).

EXAMPLE 4 1,2 dihydro-11-(trifluoromethyl)-3g,7g-quino-[8,l-cd][1,5]-benzoxazepin 3 one [2-(1-morpholinyl)ethyl] oxime, hydrochloride Amixture of 5.3 g. of the oxime (Example 1, Part II), 4.5 g. of1-(2-chloroethyl)morpholine, and 5.0 g. of powdered sodium hydroxide in80 ml. of acetone, is heated under reflux for 8 hours. The reactionmixture is cooled, filtered and the insoluble cake is washed with 20 ml.of acetone. The filtrate is concentrated to dryness and the residue isdissolved in 200 ml. of ether. The solution is washed, dried, andconcentrated in vacuo to give a residual solid. This is recrystallizedfrom hexane to give 7.8

13 g. of the colorless crystalline base, M.P. about 110-112". The baseis converted to its hydrochloride and the salt is recrystallized fromZ-PrOH to give 6.3 g. of the product, M.P. about 208-210 (dec.).

EXAMPLE 5 1,2-dihydro 3H,8H quino[1,8-ab][4,1]benzothiazepin- 3-one[Z-(N-benzyl N methylamino)ethyl]oxime, hydrochloride By following theprocedure given in Example 1, Part III, but replacing the1,2-dihydro-11-(trifluoromethyl)- 3,7-quino[8,1-cd][1,5]benzoxazepin 3one, oxime and 1-(3-chloropropyl)-4-methylpiperazine with 1,2-dihydro3g,8 I:I quino[1,8-ab] [4,1]benzothiazepin 3 one, oxime andN-(2-chloroethyl) N methylbenzylamine respectively, there is obtained1,2-dihydro 3E,8E quino [1, 8-ab] [4,1]benzothiazepin-3-one [2-(N-benzyl-N-methylamino)ethyl]oxime, hydrochloride.

1,2 dihydro-3 Ii,8E-quino[1,8-ab] [4,1]benzothiazepin- 3-one, oxime isprepared as follows:

A. 5,11 dihydrodibenzo[b,e] [1,4]thiazepine 5 propionic acid: Asuspension of 21.3 g. of 5,11-dihydrodibenzo[b,e] [1,4]thiazepine in 55ml. of acrylonitrile is cooled to -5. To this is added dropwise 0.3 ml.of Triton B. The temperature rises slowly from 3 to 14 and then rapidlyto 45 within minutes with the formation of red colored clear solution.The mixture is cooled to 5- stirred for 5 minutes, allowed to come toroom temperature and then heated under reflux for 1.5 hours. The excessof acrylonitrile is removed in vacuo; the residue is extracted with3-350 ml. portions of diethyl ether; the combined ether extracts aredecolorized and concentrated to give 27.1 g. of5,ll-dihydrodibenzo[b,e][1,4] thiazepine-5-propionitrile.

To the 5,l1-dihydrodibenzo[b,e][l,4]thiazepine-5-propionitrile, 71.1 g.in 1200 ml. of dry dioxane is added 800 ml. of 30% rnethanolic hydrogenchloride. The solution is stirred for 72 hours; 30 ml. of water isadded; the mixture is stirred for 0.5 hour, concentrated in vacuo toabout 400 ml., filtered, and the filtrate concentrated to dryness invacuo. The residue solidifies on keeping to yield methyl5,11-dihydrodibenzo [b,e] [1,4]thiazepine 5 propionate.

To the methyl 5,11 dihydrodibenzo[b,e][l,4]thiazepine-S-propionate, 25.4g., in 2200 ml. of methanol is added a solution of 5.6 g. of potassiumhydroxide in 300 ml. of water. The mixture is heated under reflux for 4hours, and then is concentrated in vacuo. The residue is taken up in 600ml. of water, cooled, and then acidified with 2% aqueous hydrochlorideacid. The solid is filtered and recrystallized from benzene to yieldill-dihydrodibenzo [b,e] [1,4] thiazepine-S-propionic acid.

B. 1,2-dihydro 328E quino[1,8-ab] [4,1]-benzothiazepin-3-one:5,l1-dihydro[b,e] [1,4]thiazepine 5 propionic acid, 3.7 g., is dissolvedin 20 ml. of benzene and to the solution at 20 is added dropwise, 2.8 g.of trifluoroacetic anhydride. The reaction mixture is heated underreflux for 5 minutes, poured into 250 ml. of cold water, and extractedwith 150 ml. of benzene. The benzene solution is concentrated todryness, and the residue is recrystallized from 2-propanol to give about2.3 g. of product.

C. 1,2-dihydro 3g,8 1 1 quino[1,8-ab] [4,1] benzothiazepine-S-one,oxime: A solution of 26.7 g. of 1,2-dihydro-3,8g-quino[1,8-ab[4,1]benzothiazepin-3-one, and 13.9 g. of hydroxylaminehydrochloride in 600 ml. of warm 70% ethanol is refluxed for 4 hours,and kept at room temperature to give a pale yellow crystalline solid.This is filtered and recrystallized from 70% ethanol to give 20.2 g. ofthe oxime.

EXAMPLE 6 1,2-dihydro 321,82 quino[1,8-ab] [4,l]benzothiazepin- 3-one,[Z-(methylamino)ethyl]oxime, dihydrobromide A solution of 18.0 g. ofl,2-dihydro-3E,8 1E I-quino[1,8- ab][4,1]benzothiazepin-3-one, [2(N-benzyl-N-methylamino)-ethyl]oxime hydrochloride (Example 5) in 500ml. of Water is made alkaline with 50% sodium hydroxide solution. Thefree amine is extracted with benzene, washed and dried. To this 9.0 g.of ethyl chloroformate is added and the mixture is heated under refluxfor 18 hours, cooled, and washed with 50 ml. of cold 5% aqueoushydrochloric acid, 50 ml. of water, dried and concentrated to give about23.0 g. of a viscous residue of the intermediate carbethoxy derivative.This is dissolved in 25 ml. of cold glacial acetic acid and to thesolution, at 10, is added 70 ml. of a 30% solution of hydrogen bromidein glacial acetic acid. The mixture is stirred at 20 for 48 hours. Tothis is added 500 ml. of anhydrous ether, when the product separates.This is isolated and washed with anhydrous ether and finally trituratedwith anhydrous acetone to give about 21.0 g. of a solid, which isrecrystallized from 2-PrOH to give about 14.0 g. of the product.

EXAMPLE 7 11-chloro-l,2 dihydro3g,8E-quino[1,8-ab][4,1]benzoxazepin-3-one, [3-(4-(2-hydroxyethyl)l-piperazinyl propyl] oxime, dimaleate I. l l-chloro-l ,2-dihydro-3,SI1-quino 1,8-ab] [4,1]- benzoxazepin-3-one A. 3-chloro-5,11dihydrodibenz[b,e][1,4]oxazepine- 5-propionic acid: A suspension of 24.4g. of 3-chloro-5, 11-dihydrodibenz[b,e] [1,4]oxazepine in 55 ml. ofacrylonitrile is cooled to 0-5. To this is added with efiicientstirring, and cooling, 0.3 ml. of Triton B, pausing after each drop ofaddition. The temperature rises slowly from 3 to 14 and then rapidly to45 within 5 minutes with the formation of red colored clear solution.The mixture is cooled to 5-10", stirred for 5 minutes, allowed to cometo room temperature and then slowly heated to reflux temperature. After1 hour heating under reflux, the excess of acrylonitrile is removed invacuo. The residue is extracted with 3-350 ml. portions of diethylether, the combined diethyl ether extracts are treated with 3.0 g. ofDarco and 1.0 g. of Hyfio, filtered, the filtrate is dried, andconcentrated to give 31.6 g. of 3-chlor0-5,11-dihydrodibenz[b,e][1,4]oxazepine S-propionitrile, B.P. aboutZOO-210 (0.2 min).

The 3-chloro-5,1 1-dihydrodibenz[b,e] [1,4] oxazepine- 5-propionitrile,71.1 g., is dissolved in 1200 ml. of dry dioxane and to this 800 ml. of30% rnethanolic hydrogen chloride is added. The solution is stirred for72 hours, 30 ml. of H 0 is added, the mixture is stirred for 0.5 hour,concentrated in vacuO to 400 ml., filtered, and the filtrateconcentrated to dryness in vacuo. The residue solidifies on keeping toyield 3-chloro-5,11-dihydrodibenz[b,e] [1,4]oxazepine-S-propionic acid,methyl ester.

The 3-chloro-5,11-dihydrodibenz[b,e] [1,4] oxazepine- S-propionic acid,methyl ester, 25.4 g., is dissolved in 2200 ml. of MeOH and to this 5.6g. of KOH dissolved in 300 ml. of B 0 is added. The solution is refluxedfor 4 hours, and then is concentrated in vacuo. The residue is taken upin 600 ml. of H 0, the solution is cooled, and then acidified with 2%aqueous HCl. The solid is filtered and dissolved in 600 ml. of C H Thissolution is treated with Darco and then extracted with 600 ml. of 2%aqueous NaOH solution. The extracts are treated with Darco and Hyflo,filtered and the filtrate is acidified with 2% aqueous HCl. The solid isfiltered and recrystallized from C H to yield 3-chloro-5,11-dihydrodibenz[b,e] [1,41oxazepine-5-propionic acid, M.P. about 138-140.

B. 11-chloro-l,2-dihydro-3g,8g quino[1,8-ab][4,1]- benzoxazepin-3-one:3.7 g. of 3-chloro-5,11-dihydro [b,e][1,4]oxazepine-S-propionic acid isdissolved in 20 ml. of warm benzene and the resulting colorless solutionis allowed to come to 30, and to this, 1.9 ml. (2.8 g.) of (CF CO) O isadded dropwise. The reaction mixture is slowly heated to reflux, thereflux is maintained for minutes, and the mixture is poured into 250 ml.of cold Water. To this, 150 ml. of benzene is added, and stirred for afew minutes. The benzene layer is separated, washed, dried, filtered,and concentrated to dryness. The residue is recrystallized first from2-propanol and then from cyclohexane to give 2.3 g. of product, M.P.about 142-144".

II. 1 l-chloro-1,2-dihydro-3,8E-quino[1,8-ab] [4,1]-

benzoxazepin-3-one, oxime A solution of 1.1 g. of the ketone fromExample 3 and 0.54 g. of hydroxylamine hydrochloride in 40 ml. of 7 0%ethanol is refluxed for 4 hours, cooled and the solid filtered. Thesolid is recrystallized from 70% ethanol to give 800 mg. of product,M.P. about 158-161 (dec.).

III. 11-ch1oro-1,2-dihydro 311,85 quino[1,8-ab] [4,1]-benzoxazepin-3-one, [3-(4-(2 hydroxyethyl)-1-piperaziny1)propyl]oxime,dimaleate A mixture of 5.1 g. of 1l-chloro-1,2dihydro-3Ii,8gquino[l,8-ab] [4,1]benzoxazepin-3-one, oxime, 7.2 g. of1-bromo-3-chloropropane, 5.0 g. of powdered sodium hydroxide in 100 m1.of Z-butanone is heated while stirring under reflux for 24 hours. Themixture is cooled, and slowly, while stirring, ml. of B 0 is added. Theaqueous phase is separated and extracted with ml. of 2- butanone. Thecombined 2-butanone extracts are concentrated to dryness in vacuo, theresidue is dissolved in 100 ml. of toluene, and the solution is treatedwith 4.1 g. of l-piperazine-ethanol, followed by 5.6 g. of K CO and 0.3g. of copper bronze. The mixture is heated under reflux for 8 hours,cooled, filtered and the filtrate concentrated to dryness in vacuo togive 8.0 g. of residue. This is dissolved in 100 ml. of Z-PrOH and tothis is added a solution of 3.5 g. of maleic acid in 20 ml. of Z-PrOI-I.The crystalline solid that separates is recrystallized from 2- PrOH togive 8.9 g. of the product.

EXAMPLE 8 1,2 dihydro-1l-(trifluoromethyl)GEJg-quinMSJ-cd] [1,5-benzoxazepin-3-one, [Z-(dimethylamino ethyl] oxime hydrochloride Amixture of 9.6- g. of 1,2-dihydro-1l-(trifiuoromethyl)-3 ,7E-quino[8,lcd] [1,51benzoxazepin-3-one, 11.4 g. of fl-dimethylaminoethoxyaminedihydrochloride, 20 ml. of pyridine, and ml. of absolute ethanol isrefluxed for 24 hours and then concentrated to dryness in vacuo. Theresidue is warmed with 100 ml. of 2 N aqueous hydrochloric acid, thencooled, made alkaline with aqueous NaOH and the oil extracted with 300ml. of ether. The ether solution is treated with 15 ml. of 4.8 N2-propanolic hydrogen chloride, the solid is filtered and recrystallizedfrom 2-propanol to give 10.8 g. of the product, M.P. about 218220(dec.).

EXAMPLE 9 1,2 dihydro-1l-(trifluoromethyl)-3g,7 I -quino[8,1-cd] [1,5]benzoxazepine-3-one, [2- (4-methyl)1-piperazinyl)ethyl]oxime,dihydrochloride By following the procedure described in Example 1, butreplacing the l-(3-chloropropyl)-4-methylpiperazine with1-(Z-chloroethyl)-4-methylpiperazine, there is obtained the product,M.P. about 241-243 (dec.).

EXAMPLE 10 1,2 dihydro-1l-(trifluoromethyl)-3,7 Ii-quino[8,l-cdl [1,5]benzoxazepin-3-one, [2-(l-piperidinyl)ethyl] oxime, hydrochloride Byfollowing the procedure described in Example 1, but replacing the1-(3-chloropropyl)-4-methylpiperazine with 1-(2-chloroethyl)piperidine,there is obtained the product, M.P. about 211-213 (dec.).

EXAMPLE 11 1,2 dihydro-1l-(trifiuoromethyl)-3I ,7E-quino[8,l-cd] 1,5]-benzoxazepin-3-one, [2- (hexahydrolIi-azepin-lyl) ethyl] oxime,hydrochloride Following the procedure described in Example 1, butsubstituting 1-(3-chloropropyl)-4-methylpipcrazine withl-(2-chloroethyl)hexahydro-lIi-azepine, there is obtained the titleproduct, M.P. about 198-200 (dec.).

EXAMPLE 12 1,2 dihydro-11-(trifiuoromethyl)-3g,7E-quino[8,1-cd][1,51-benzoxazepine 3 one,[2-(dimethylamino)-2- methylethyl] oxime,oxalate By following the method described in Example 4, but replacingthe 1-(2-chloroethyl)morpholine with dimethylaminoisopropyl chloride,there is obtained the base, and this then is converted to the oxalate.The latter, on recrystallization from ethyl acetate gives the product,M.P. about 105-108" (dec.).

EXAMPLE l3 1,2-dihydro 11 (trifluoromethyl)-3E,7 11-quino[8,1-cd] [1,5]benzoxazepine-3-one, [Z-(N-benzyl-N-methyl) amino ethyl] -oxime,hydrochloride By following the procedure in Example 1, but substitutingthe 1-(3-chloropropyl)-4-methylpiperazine with N-(2- chloroethyl)-N-methyl beuzylarnine, there is obtained the product, M.P. about184-186" (dec.).

EXAMPLE l4 4-chloro 1,2 dihydro 353g quino[l,8-ab] [4,1] benzoxazepin 3one[3 (dimethylamino)propyl] oxime, hydrochloride By following theprocedure given in Example 3, but substituting 1,2dihydro-ll-(trifluoromethyD-Bgflgquino[8,1-cd] [1,5]benzoxazepin-3-one,oxime with 4- chloro 1,2 dihydro-3,8g-quino[1,8-ab][4,11benzoxazepin-3-one, oxime, there is obtained 4-chloro-l,2-dihydro-3H ,8E-quino[1,8-ab] [4,1]benzoxazepin 3 one,[3- (dimethylamino -propyl]oxime hydrochloride. 4-Chloro- 1,2-dihydro BEBE quino[l,8-ab][4,11benzoxazepin- 3-one, oxime is prepared as follows:

A suspension of 17.4 g. of 7-chloro-5,11-dihydrodibenz [b,e][l,4]oxazepine in 35 ml. of acrylonitrile is cooled to 0-5. To this isadded with eflicient stirring and cooling 0.2 m1. of Triton B. Thesuspension becomes homogeneous and a red solution results with the riseof temperature to 10. The reaction mixture is allowed to come to roomtemperature and then refluxed for one hour with stirring. The excess ofacrylouitrile is removed by known means, water is added, and the solidis filtered. The solid is dried, powdered, and extracted with five 400ml. portions of diethyl ether. The diethyl ether extracts are dried andconcentrated to a volume of 250 ml. The white crystalline compound isfiltered. The filtrate is again concentrated and the resulting solid isfiltered. The yield of the combined desired products (i.e.,7-chloro-5,11-dihydrodibenz[b,e]-[1,4]oxazepine-5-propionitrile) is 21.5g., NLP. about 131-132.

The 7-chloro-5,11 dihydrodibenz[b,e] [1,4]oxazepine- 5-propionitrile,71.10 g., is dissolved in 1200 nfl. of dry dioxane and to this 800 ml.of 30% methanolic hydrogen chloride is added. The solution is stirredfor 72 hours, 30 ml. of water is added, the mixture is stirred for 0.5hour, concentrated in vacuo to 400 ml., filtered, and the filtrateconcentrated to dryness in vacuo. The residue solidifies on keeping toyield 7-chloro-5,11 dihydrodibenz[b,e] [1,4] oxazepine-S-propionic acid,methyl ester, 67.5 g., M.P. about -72".

The 7-chloro-5,11-dihydrodibenz[b,e] [1,4]oxazepine-5- propionic acid,methyl ester, 25.4 g., is dissolved in 2200 17 ml. of MeOH and to this5.6 g. of KOH dissolved in 300 ml. of water is added. The solution isrefluxed for 4 hours, and then is concentrated in vacuo. The residue istaken up in 600 ml. of water, the solution is cooled, and then acidifiedwith 2% aqueous HCl. The solid is filtered and dissolved in 600 ml. of CH This solution is treated with Darco and then extracted with 600 ml. of2% aqueous NaOH solution. The extracts are treated with Darco and Hyflo,filtered and the filtrate is acidified with 2% aqueous HCl. The solid isfiltered and recrystallized from C H The yield of7-chloro-5,11-dihydrodibenz[b,e]-[1,4]oxazepine-S-propionic acid is 23.0g. M.P. about 15 5 .0-15 6.5

A solution of 7.35 g. of 7-chloro-5,1l-dihydrodibenz-[b,e][1,4]oxazepine-5-propionic acid in 40 ml. of warm benzene is slowlycooled to 35 and while stirring 3.8 ml. of (CF CO) is added dropwise.The reaction mixture is heated to reflux and the reflux is maintainedfor minutes. To this 50 ml. of benzene is added and the solution ispoured into cold water. The yellow benzene layer is separated and theaqueous phase is extracted with 50 ml of benzene. The combined benzeneextracts are washed, dried, and concentrated to dryness under reducedpressure. The residue solidifies to an intense yellow material, whichweighs about 7.0 g., M.P. about 110-120. This solid is dissolved in 325ml. of a refluxing mixture of 2-propanol and cyclohexane (2:3), and keptat room temperature for two days, when two diflerent kinds of crystalsform. These are filtered and the intense yellow transparent rhombiccrystals (compound A) are separated manually from the darker yellow flatneedles (compound B). Compound A melts at about 140-142 and weighs about1.3 g. while compound B melts at 137-143 and weighs about 3.4 g.

Compound A, 1.3 g. is dissolved in 75 ml. of a refluxing mixture of2-propanol and cyclohexane (1 :4), filtered, and kept at roomtemperature. This gives about 1.1 g. of intense yellow transparentneedles M.P. about l40-142.5. This compound is shown to be11-chloro-l,2-dihydro-3I i, 7g-quino [8,1-cd] [1,5 benzoxazepine-3-one.

Compound B is dissolved in 225 ml. of a refluxing mixture of 2-propanoland cyclohexane (1:4), filtered and kept at room temperature to giveabout 2.7 g. of darker yellow non-transparent long needles, M.P. about141.5- 144. This compound is shown to be 4-chloro-1,2-dihydro-3g,8g-[1,8-ab] [4,1]benzoxazepin-3-one.

1l-chloro-1,2-dihydro-31j,7-quino[8,1-cd] [1,5] benzoxazepin-3-one,oxime A mixture of 36.0 g. of 1l-chloro-1,2-dihydro-3I ,7gquino[8,1-cd][1,5 ]benzoxazepine 3 one (Compound A from Example 12) and 17.5 g. ofhydroxylamine hydrochloride is dissolved in 2 liters of warm 70% ethanoland refluxed for three hours. The reaction mixture is concentrated to1.5 liters and allowed to cool. The resulting pale yellow needles arefiltered and recrystallized from 70% ethanol to give about 28.5 g. ofproduct, M.P. about 224- 226 (dec.).

4-chloro-l,2-dihydro-3g, 8 I -quino[1,8-ab] [4, 1] benzoxazepin-3-one,oxime A mixture of 13.0 g. of 4-chloro-1,2-dihydro-3E,8g quino[1,8 ab][4,1]benzoxazepin 3 one (Compound B from Example 12), and 6.3 g. ofhydroxylamine hydrochloride in 1400 ml. of warm 70% ethanol is refluxedfor three hours. The reaction mixture is allowed to cool. The resultingpale yellow needles are filtered and recrystallized from 80% ethanol togive about 11.0 g. of product, M.P. about 252-254 (dec.).

EXAMPLE 15 11 chloro 1,2 dihydro 3g,7g quino[8,1-cd] [1,5]benzoxazepin-3-one [2-(1-pyrrolidinyl)ethyl] oxime hydrochloride Byfollowing the procedure described in Example 2, but

replacing the 1,2-dihydro-11-(trifluoromethyl)-3 l,7-

1 8 quino[8, l-cd] [1,5 ]benzoxazepin-3-one oxime with the corresponding1 l-chloro analog [prepared as in Example 12 (Compound A) there isobtained the product.

EXAMPLE 16 1,2 diliydro-3g,8gquino[1,8-ab] [4,1]benzoxazepin-3-one-[3-(4-(2-hydroxyethyl) 1 piperazinyl)propyl] oxime dimaleate Byfollowing the procedure given in Example 7, but replacing the11-chl0ro-1,2-3 11,8l-I -quino[1,8-ab] [4,1] benzoxazepin-3-one oximewith 1,2-dihydro-3ESE-quino [1,8-ab] [4,1]benzoxazepin-3-one oxime,there is obtained the product.

The 1,2 dihydro-3E,8 I -quino[1,8-ab] [4,1]benzoxazepin-3-one oxime isprepared as follows:

I. 1,2-dihydro-3 I I 8 11-quino[1,2-ab] [4,1]benzoxazepin 3- one A.5,11-dihydrodibenz[b,e] [1,4]oxazepine-5 propionic acid: A suspension of30.4 g. of 5,11-dihydrodibenz [b,e] [1,4] oxazepine in ml. ofacrylonitrile is cooled to 0-5 To this is added with eflicient stirringand cooling 0.9 ml. of Triton B. The suspension becomes homogeneous anda red solution results with the rise of temperature to 10. The reactionmixture is allowed to come to room temperature and then refluxed for onehour with stirring. The excess of acrylonitrile is removed by knownmeans, water is added, and the solid is filtered. The solid is dried,powdered, and extracted with five 400 ml. portions of diethyl ether. Thediethyl ether extracts are dried and concentrated to a volume of 250 ml.The white crystalline compound is filtered. The filtrate is againconcentrated and the resulting solid is filtered and found to melt atabout l38l39.5, and is identified as 5,11-dihydrodibenz[b,e] [1, 4]oxazepine-S-propionitrile.

The 5,11-dihydrodibenz[b,e] [1,4]oxazepine-5,1l-propionitrile, 5.0 g.,is dissolved in 200 ml. of methanol and to this 2.24 g. of potassiumhydroxide dissolved in 20 ml. of water is added. The solution isrefluxed for 4 hours, and then is concentrated in vacuo. The resdiue istaken up in 600 ml. of H 0, the solution is cooled, and then acidifiedwith 2% aqueous HCl. The solid is filtered and dissolved in 600 ml .of CH This solution is treated with Darco and then extracted with 600 ml. of2% aqueous NaOH solution. The extracts are treated with Darco and Hyflo,filtered and the filtrate is acidified with 2% aqueous HCl. The solid isfiltered and recrystallized from C H and found to have a M.P. of about203-205".

B. 1,2-dihydro-3g,8g-quino[1, 8-ab] [4,1]benzoxazepin- 3-one: In a 500ml. flask equipped with stirring bar, thermometer, nitrogen inlet,dropping funnel and CaCl guard tube, is suspended 10.8 g. of5,11-dihydrodibenz[b, e][1,4]oxazepine-5-propionic acid in 220 ml. of CH This is cooled to 10, and to it is added a solution of 9.5 g. of P01in 50 ml. of benzene in 45 minutes. The reaction mixture is stirred for1.5 hour at room temperature. To the resulting solution, 5.5 g. ofsodium hydrosulfite is added and stirred for 15 minutes. The reactionmixture is filtered and the filtrate is concentrated in vacuo to yield aliquid residue. The residue is triturated with 70 ml. of petroleum etherto give a yellow solid, which is filtered. Of the acid chloride residue(9.6 g.), 8.6 g. are dissolved immediately in 220 ml. of benzene.

One gram of the above crude acid chloride is dissolved in ml. of boilingpetroleum ether, filtered, the filtrate treated with 0.2 g. of Darco,refluxed, and filtered again. This is stored overnight in the cold room.Crystallization does not occur. The solution is concentrated to 50 m1.and cooled in an acetone-CO bath, when a pale yellow solid separates.This is filtered and dried in vacuo for 15 minutes; it softens at 60 andmelts with decomposition at about 74-75".

The above solution of 8.6 g. of the acid chloride in 220 ml. of benzeneis placed in a flask equipped with a stirrer, a dropping funnel, and areflux condenser guarded with a CaCl, tube. To this, while stirring, isadded dropwise, a solution of 9.0 ml. of anhydrous SnCL, in 50 ml. ofbenzene. A viscous red complex forms which turns to violet towards theend of the addition. The reaction mixture is stirred for 1 hour and then600 ml. if ether is added. To this, 20 ml. of cone. HCl and 150 m1. ofdistilled H O are added and the mixture stirred vigorously for 1 hour.The organic phase is separated, washed, filtered, and solvent removedand the residue is extracted successively with 300, 200 and 200 ml.portions of boiling cyclohexane. The combined cyclohexane extracts areconcentrated to 75 ml. to give 2.9 g. of product, M.P. abou-t 116-118.

'I I. 1,2-dihydro-3g,7 I-quino[8,l-cd] [1,51benzoxazepin- 3-one, oxirneA mixture of 1.25 g. of 1,2-dihydro-3g,8g-quino[1,8- ab}[1,5]benzoxazepin-3-one and 0.7 g. of hydroxylamine hydrochloride isdissolved in 140 ml. of hot 70% ethanol and refluxed for 6 hours; thereaction mixture is concentrated on the Rinco to 60 ml., when a yellowprecipitate forms. After standing overnight in the cold room, yellowsolid toms which is filtered and dried to give 1.35 g. of material; M.P.softens at 155 and melts with decomposition at 170. It is dissolved in125 ml. of refluxing 75% ethanol, treated with 0.2 g. of Darco andfiltered to give 1.2 g. of product, M.P. about 190-192.

EXAMPLE l7 11-cyano-1,2-dihydro-3g,7g quino[8, 1cd][1,5]benzoxazepin-3-one (2-dimethylaminoethyl)oxime, hydrochloride Byfollowing the procedure described in Example 8, and replacing the1,2-dihydro-11 (trifluoromethyl) 32,711- quino[8,l-cd][l,5]benzoxazepin-3-one oxime with the corresponding ll-cyanoderivative, there is obtained 11- cyano-1,2-dihydro-3gJg-quino[8,1 cd][1,5]benzoxazepin-3-one (2-dimethylaminoethyl)oxime hydrochloride. The11-cyano-1,2-dihydro-3 1,7 I E[ quino[8,1 cd][l,5] benzoxazepin-3-one,oxime is prepared as follows:

A. 7-cyano-5,11-dihydrodibenz[b,e] [1,4]oxazepine 5- propionic acid: To44.4 g. of 7-cyano-5,ll-dihydrodibenzo [b,e] [1,41oxazepine in 60 ml. ofacrylonitrile is added 0.80 ml. of Triton B. The mixture is heated forone hour under reflux and the product isolated by extraction withbenzene to give 7-cyano-5,11-dihydrodibenz[b,e] [l,4]oxazepine-5-propionitrile.

To 13.7 g. of 7-cyano-5,l1-dihydrodibenz[b,e][1,4]-oxazepine-S-propionitrile in 240 ml. of dioxane is added 140 m1. of 30%methanolic hydrogen chloride. The solution is kept for 36 hours, 6 ml.of H is added, and then concentrated in vacuo to about 120 ml.,filtered, and the filtrate concentrated in vacuo. The residual liquid isdissolved in 200 m1. of diethyl ether, the ether solution isconcentrated and the residue distilled in vacuo to give methyl 7cyano-5,1l-dihydrodibenz[b,e] 1,4]oxazepine- S-propionate, B.P. about170-172 (0.08 mm.).

To methyl 7 -cyano-5,11-dihydrodihenz[b,e] {1,4]oxazepine-S-propionate,3.1 g., in 315 ml. of methanol, is added 0.6 g. of potassium hydroxidein 25 ml. of Water. The

. mixture is refluxed for 2.5 hours and then concentrated in vacuo. Theresidue is dissolved in 25 0 m1. of water and treated with an excess of2% aqueous hydrochloric acid to give 7-cyano-5,11dihydrodibenz[b,e][l,4]oxazepine- S-propionic acid.

B. 11 cyano 1,2 dihydro BEJE quino[8,1-cd]- [1,5]-benzoxazepine-3-one:To 6.33 g. of 7-cyano-5,11- dihydrodibenz[b,e] [1,4]oxazepine-S-propionic acid in 50 ml. of benzene at -10 is added 4.6 g.of phosphorus pentachloride in 25 ml. of benzene during 15 minutes. Thesolution is stirred at 25 for 40 minutes, at 40-50" for 20 minutes, at55 for minutes, cooled and treated dropwise with 12.0 g. of anhydrousstannic chloride in 20- oxazepine-3-one, and 17.5 g. of hydroxylaminehydrochloride is dissolved in 2 liters of warm 70% ethanoland refluxedfor three hours. The reaction mixture is concentrated to 1.5 liters andallowed to cool. The resulting pale yellow needles are filtered andrecrystallized from 70% ethanol to give about 28.5 g. of product.

EXAMPLE 18 ll-chloro 1,2 dihydro-3 ,8E-quino[1,8-ab][4,1]benzoxazepin-3-one, [2-(4-methyl 1 piperazinyl)ethy1]-' oximedihydrochloride Following the method described for Example 1 butreplacing the 1,2-dihydro 11 (trifluoromethyl) 62,711- qino-[8,t-cd][1,5 ]benzoxazepin-3-one oxime and 1 (3-chloropropyl)-4-methylpiperazine with 11- chloro-1,2-dihydro sgsgquino[1,8-ab] [4,1]benzoxazepin 3 one oxime and1-(2-chloroethyl)-4-methylpiperazine, respectively, there is obtainedll-chloro 1,2 dihydro-3,8 l 1 quino [1,8-ab] [4,l1benzoxazepin 3 one, [2(4- methyl-l-piperazinyl)ethyl] oxirne dihydrochloride.

EXAMPLE 19 a 1 ll-chloro 1,2 dihydroEJE-quino[8,1-cd][1,5]benzoxazepin-3-one, [3-(methylamino)propyl]oxime, hydrochloride A.To 23.4 g. of sodium amide in 400 ml. of anhydrous toluene, undernitrogen and at 0-5", is added dropwise 31.9 g. of N-methyl formamide in100 ml. of anhydrous toluene; the mixture is stirred for 2 hours at 25and then 94.6 g. of trimethylenechlorbrornide is added dropwise, and themixture heated under reflux for 4 hours; the re action mixture iscooled, filtered and the filtrate concentrated in vacuo. The liquidresidue on distillation in vacuo gives 12.2 g. ofN-(3-chloropropyl)-N-rnethylformamide, bag about 148-150.

Following the procedure of Example I, part IE, but replacing 1,2dihydro-11-(trifluoromethyl)-3,7g-quino- [8,l-cd}[1,5]benzoxazepin-3-one oxime and 1-(3-chloropropyl)-4-methylpiperazinewith 9.4 g. of 1l-chloro-1,2- dihydro-3I ,7 I1-quino[8,l-cd][1,5]benzoxazepin 3 one, oxime and 8.2 g. of-N-(3-chloropropyl)-N-methylformamide respectively, there is obtained10.7 g. of ll-chloro- 1,2-dihydro 3g,7g quino[8,1-cd][1,51benzoxazepin-3- one [3-(N-formyl-N-methylamino)propyl] oxime, as abase. This is dissolved in 300 ml. of ethanol and to it 26 ml. of 20%aqueous hydrochloric acid is added. The mixture is heated under refluxfor 3 hours, and concentrated to dryness in vacuo. To the residue 500ml. of water is added, the solution washed with ether, and then treatedwith an excess of 50% aqueous NaOH; the liberated oil is isolated viaether extraction, which is treated with 2- propanolic hydrogen chlorideto give 6.3 g. of ll-chloro- 1,2 dihydro 3,7 I1 quino[8,1 cd][1,51benzoxazepin- 3-one, [3-methylamino)propyl] oxime, hydrochloride.

EXAMPLES 20 TO 34 Employing the procedures described in Example 1, butsubstituting the starting material shown in column A of 33 What isclaimed is: 1. A compound having the structure wherein X istrifluoromethyl or chloro, n is an integer of from 1 to 6, R is loweralkyl or hydroxy-lower alkyl, wherein lower alkyl is an alkyl grouphaving up to eight carbon atoms, and a non-toxic acid-addition saltthereof.

2. A compound in accordance with claim 1 wherein X is chloro.

3. A compound in accordance with claim 1 wherein X is trifluoromethyl.

4. A compound in accordance with claim 1 wherein R is lower alkyl.

5. The compound in accordance with claim 1 having the name 1,2-dihydro-l1- (trifluoromethyl -3H,7H-quino 8, 1- cd] [1,5]benzoxazepin-3-one,[3-(4-methyl-1-piperazinyl) propy1]oxime.

6. The compound in accordance with claim 3 having the name 1,2dihydro-l1-(trifluoromethyl)-3H,7H-quino[8,1- cd][1,51benzoxazpein-3-one, [3-(4-methy1-1-piperazinyl) ethyl]oxime.

7. A compound in accordance with claim 1 having the structure 34 whereinn is 2 or 3.

8. A compound having the structure O-CH:

References Cited UNITED STATES PATENTS 3,676,445 7/1972 Yale et a1.260-288 DONALD G. DAUS, Primary Examiner US. Cl. X.R.

260--239 BC, 243 C, 247.1, 247.5 B, 293.57, 293.58, 2830 N, 2835', 2835A, 288 R, 326.5 CA, 327 B, 333, 999

Column Column Column Column Column Column Column Column Part I of 2Patent No.

Inventor(s) 3,813,396 Dated May 28, 1974 HarryL. Yale and Ramesh B.Petigara It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

2, Formula II, that portion of the formula reading:

N should be:

, .a 1 3 2 2 NOZ NR NOZNR R line 38, the words "starting material II"should be: starting material III lines 68 to 75, the structure should belabeled: (IV) 3 line 69, the number "II" should be: III

line 23, that portion reading: "dihydrodizenz" should be: dihydrodibenzline 61, delete the right parenthesis after LCH cH the word "methyl".

linel9, that portion reading: "[l,2-ab]" should be: [l,8-ab] Example 20,Column A, that portion of the formula reading:

should be: L J N I CH CH COOH l CH CH COOH ORM PO-IOSO (10-69) USCOMM-DC60376-F'69 x: u.s. GOVERNMENT PRINTING OFFICE I969 0-365-334,

Part 2 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION gate, N3,813,396 Dated May 28, 1974 Inventor(s) Harry L. Yale and Ramesh B.Pe'tigara It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

Columni26, the example after "31" should be: 32

Column 29, Example 36, Column D, that portion of the formula reading:

' should be Signed and sealed this 1st day of October 1974.

(SEAL) AttBst:

McCOY M. GIBSON JR. C. MARSHALL DANN Commissioner of Patents .Attesting'Officer USCOMM-DC fl0376-P69 U.S. GOVERNMENT PRINTING OFFICE l9,0-366-33,

F ORM PO-105O (10-69)

